Vulnerable plaques are prone to rupture and can cause acute coronary syndromes. The goals of these 3 collaborative projects are to identify the mechanisms related to the formation and stabilization of vulnerable plaques and to develop non-invasive methods for their detection and characterization. Project 1 focuses on the protective effects of HDL. In aims 1 and 2, mouse models of human atherosclerosis will be used to identify the mechanisms by which HDL can retard the progression of plaque formation (aim 1) or promote the regression and stabilization of established lesions (aim 2). To elevate HDL levels after lesions are established, strategies based on transplant surgery and gene transfer will be used. In aim 3, magnetic resonance imaging (MRI), capable of noninvasively characterizing advanced lesions in mouse abdominal aorta, will be further developed to serially assess lesion changes in mice (from Projects 1 and 2) during plaque progression, regression, or stabilization. Project 2 focuses on the central role of the macrophage in plaque formation and de-stabilization. Aim 1 will examine the potential of dexamethasone (Dex) to affect plaque progression/regression and the expression of monocyte chemoattractant protein-1 (MCP-1; a pro- atherogenic product of macrophages) in induced mutant mouse models treated by diet or vessel injury. Aim 2 will focus on the molecular regulation of Dex-induced instability of MCP-1 mRNA. In aim 3, a novel mouse model will be developed and studied in which macrophages can be specifically ablated at selected time points to determine their importance in plaque progression, regression, and, importantly, rupture. Project 3 will characterize vulnerable plaques by MRI in humans. In aim 1, asymptomatic patients with dyslipidemia and patients with stroke will be screened for plaques in the thoracic aorta and carotid arteries. Plasma lipid levels will be modified by therapy with a statin or statin plus niacin (to raise HDL) and changes in plaque size and composition will be followed serially by MRI. In aim 2, a porcine model of human coronary artery disease will be used to develop MRI techniques to detect and characterize coronary plaques, then these techniques will be applied to humans. Overall, the 3 projects represent highly interactive efforts of experienced investigators who will develop new approaches to the vulnerable plaque using molecular biology, animal models, clinical investigation, and MRI.